The goals of this project are to characterize the pathogenesis, natural history and therapy of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Our clinical emphasis has been on oral and genital herpes and zoster in the normal and the immuno-compromised host. Over the years we established the value, long term efficacy and safety of oral acyclovir for suppression of recurrent genital herpes and more recently oral herpes as well. We are conducting collaborative studies of BVaraU, a new drug for zoster. We continue to seek evidence of persistent acyclovir-resistant HSV infections in immunologically normal individual. The major basic research thrust of this laboratory has been to define molecular aspects of HSV and VZV latency and pathogenesis. We are examining the role of the HSV 1 and 2 latency-associated transcripts (LAT) in control of virus latency and reactivation. Recombinant viruses deleted for LAT expression and which contain targeted mutations in the LAT promoter are being studied in vitro and in animal models. We have begun to create transgenic mice expressing HSV genes neighboring and/or including the LAT gene. This past year we established mouse ocular models of acute and latent HSV1 and HSV2 infection so that the comparative pathogenesis of these infections can be studied. Work on VZV latency and gene regulation has concentrated on genes 4, 10, 28, 21, 61, 62, and 63. Because gene 29 is expressed in latency and 28 is not, we are studying the regulation of these two genes. We found that they share a common and overlapping promoter.